Plasma sphingolipids and risk of cardiovascular disease

血浆鞘脂与心血管疾病的风险

基本信息

批准号：
9253248
负责人：
Rozenn Lemaitre
金额：
$ 58.74万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-15 至 2019-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9253248
关键词：
Aging Animal Experiments Apoptosis Arrhythmia Atrial Fibrillation Biological Brain natriuretic peptide C-reactive protein Carbon Cardiac Myocytes Cardiovascular Diseases Cells Ceramides Cessation of life Characteristics Cohort Studies Data Diet Dietary Factors Disease Drug Targeting Echocardiography Elderly Engineering Environmental Risk Factor Exhibits Fatty Acids Fibrinogen Functional disorder Funding Future Heart Abnormalities Heart failure Human Incidence Inflammation Injury Ischemia Knockout Mice Left Left Ventricular Dysfunction Left Ventricular Mass Length Life Style Lipids Liquid Chromatography Mass Spectrum Analysis Measures Mediator of activation protein Morbidity - disease rate N-terminal National Heart, Lung, and Blood Institute Oxidative Stress Palmitic Acids Participant Pharmaceutical Preparations Phenotype Phospholipids Physical activity Physiological Plasma Play Population Prevalence Prevention Prospective cohort study Reperfusion Therapy Risk Risk Factors Role Sampling Saturated Fatty Acids Smoking Sphingolipids Sphingomyelins Stress Tobacco Troponin Ventricular Work cardiovascular disorder risk cardiovascular health cardiovascular risk factor disorder risk drug development fight against fighting follow-up high risk inflammatory marker mortality new therapeutic target novel phenotypic biomarker pi bond population based prospective public health relevance sudden cardiac death

项目摘要

DESCRIPTION (provided by applicant): This application seeks to identify novel modifiable factors, plasma ceramide and sphingomyelin species, associated with risks of incident heart failure (HF), incident atrial fibrillation (AF), incident sudden cardiac death (SCD) and total mortality. Ceramides and sphingomyelins are cell and circulating lipids that are involved in apoptosis, oxidative stress, ischemia/reperfusion and other mechanisms of relevance to the pathophysiology of HF and arrhythmias. Until recently, all ceramides and sphingomyelins were thought to have similar physiological effects and most studies investigated total levels; however, there is now compelling evidence that species that carry saturated fatty acids of different length exhibit divergent biological activities. These studies provide a strong basis for our hypothesis that higher plasma levels of ceramide and sphingomyelin species that carry the fatty acid 16:0 (16 carbons, 0 double bond) are associated with higher risks of incident HF, AF and SCD, and higher total mortality; and higher plasma levels of ceramide and sphingomyelin species that carry the fatty acids 20:0, 22:0 or 24:0 are associated with lower risks of incident HF, AF and SCD, and lower total mortality. We will investigate these novel hypotheses in the Cardiovascular Health Study (CHS), an NHLBI-funded prospective cohort study of risk factors for cardiovascular disease among older adults. We will measure ceramide and sphingomyelin species in existing plasma samples using liquid chromatography followed by mass spectrometry. Plasma samples collected in 1992 are available on about 3800 CHS participants. We will combine the new data with existing extensive information on risk factors and follow-up data from 1992 to 2011. In Primary Aims, we will investigate the associations of plasma ceramide and sphingomyelin species containing 16:0, 20:0, 22:0, and 24:0 with the risks of incident HF (Aim1), incident AF (Aim 2), incident SCD (Aim 3) and with total and cardiovascular disease mortality (Aim 4). During follow-up, 968 incident HF, 978 incident AF, 200 incident SCD and 2788 deaths have been identified. In Secondary Aims, we will investigate the associations of the ceramide and sphingomyelin species with intermediate endpoints including left ventricular mass from echocardiography, electrocardiographic phenotypes, and markers of left ventricular stress, cardiomyocyte injury and inflammation (Secondary Aim 1); we will also investigate life- style predictors of levels of the ceramide and sphingomyelin species, including medications, dietary factors, smoking and physical activity measured before the 1992 exam (Secondary Aim 2). This study will comprehensively examine the associations of novel modifiable molecules, ceramide and sphingomyelin species, with incidence and mediators of HF and arrhythmia, mortality, and life-style characteristics. Little is known about potential divergent effects of distinct ceramde and sphingomyelin species in humans. The study will inform novel drug targets and novel prevention efforts in the fight against HF and arrhythmia.

描述（由应用提供）：本应用程序旨在鉴定与事件心力衰竭风险（HF），入射房颤（AF），入射心脏死亡（SCD）和总死亡率相关的新型可修改因素，血浆神经酰胺和鞘磷脂物种。神经酰胺和鞘磷脂是细胞和循环脂质，与凋亡，氧化应激，缺血/再灌注以及与HF和心律失常的病理生理学相关的其他机制。直到最近，所有神经酰胺和鞘胺的物理作用都相似，大多数研究都研究了总水平。然而，现在有令人信服的证据表明，携带具有不同长度的暴露于不同生物学活性的饱和脂肪酸的物种。这些研究为我们的假设提供了有力的基础，即携带脂肪酸16：0的较高的血浆神经酰胺和鞘磷脂物种水平（16碳，0双键）与较高的HF，AF和SCD的风险相关，以及较高的总死亡率。以及携带脂肪酸20：0、22：0或24：0的神经酰胺和鞘磷脂物种的较高血浆水平与较低的HF，AF和SCD的风险较低以及总死亡率有关。我们将在心血管健康研究（CHS）中调查这些新的假设，这是NHLBI资助的前瞻性队列研究，研究了老年人心血管疾病的危险因素。我们将使用液相色谱法测量现有血浆样品中的神经酰胺和鞘磷脂物种，然后测量质谱法。 1992年收集的血浆样品可在约3800个CHS参与者中获得。我们将将新数据与1992年至2011年的风险因素和后续数据相结合。在主要目的中，我们将调查含有16：0、20：0、20：0、22：0、22：0和24：0的血浆神经酰胺和鞘磷脂的关联与事件HF（AIM1）的风险（AIM 1），AIM 2），AIM 2），AIM scd（AIM AIM 3）和CARD（目标3）。在随访期间，已经确定了968例HF，978事件AF，200例SCD和2788人死亡。在次要目的中，我们将研究神经酰胺和鞘氨质素种与中间端点的关联，包括超声心动图，心电图表型以及左心室应激，心肌细胞损伤和感染的左心室质量（次要目标1）；我们还将研究神经酰胺和鞘磷脂物种水平的生活方式预测指标，包括药物，饮食因素，吸烟和1992年考试之前测量的体育锻炼（次要目标2）。这项研究将全面研究新型可修改分子，神经酰胺和鞘磷脂物种的关联，以及HF和心律不齐的介体，死亡率，死亡率，死亡率，和生活方式的特征。关于人类中不同的ceramde和鞘氨质种类的潜在分歧作用知之甚少。该研究将为对抗HF和心律不齐的斗争中的新型药物靶标和新的预防工作提供信息。